Is THRB p.Pro452Ser (c.1354C>T) pathogenic?

THRB p.Pro452Ser (c.1354C>T) is classified Conflicting classifications of pathogenicity in THRB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-03-04). AlphaMissense: likely pathogenic (0.9891); Absent from gnomAD v4.1; Associated with THRB-related disorder.

What condition is associated with THRB p.Pro452Ser (c.1354C>T)?

THRB p.Pro452Ser (c.1354C>T) is associated with THRB-related disorder, thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

How common is THRB p.Pro452Ser (c.1354C>T) in the general population?

THRB p.Pro452Ser (c.1354C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about THRB p.Pro452Ser (c.1354C>T)?

AlphaMissense predicts likely pathogenic (score 0.9891) — an in-silico prediction, not a clinical call.

THRB p.Pro452Ser

c.1354C>T · rs2148780678 · VCV1705477

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9891 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

THRB-related disorder

Computational evidence

Protein change
AlphaMissense	0.9891	likely pathogenic
REVEL	0.86	moderately pathogenic-leaning
SaProt	LLR -9.46	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.15	constrained · MANE · 103 bp · p 5.9e-09 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: THRB
Protein: p.Pro452Ser
Coding: c.1354C>T
MANE Select: NM_001354712
dbSNP: rs2148780678
Type: single nucleotide variant
Location: chr3:24122916 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 452: the nr lbd domain; the 'interaction with nr2f6' region

Full THRB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

THRB-related disorder

Also linked: thyroid hormone resistance, generalized, autosomal dominant

Similar variants

THRB p.Pro452Thr Uncertain significance ★ ⚠ same residue
THRB p.Pro452Arg Uncertain significance ★ ⚠ same residue
THRB p.Pro452= Likely benign ★ same residue
THRB p.Ala268Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
THRB p.Ala317Thr Pathogenic ★★ ⚠ same condition
THRB p.Arg316His Pathogenic ★★ same condition
THRB p.Arg320Cys Pathogenic ★★ same condition
THRB p.Arg320His Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/thrb-p-pro452ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown